Dibenzocycloheptenes and processes for the preparation thereof



United States Patent Ofitice 3,312,738 Patented Apr. 4, 1967 3,312,738DIBENZOCYCLOHEPTENES AND PROCESSES FOR THE PREPARATION THEREOF MaxTishler, Westfield, John M. Chemerda, Metuchen, and Janos Kollonitsch,Westfield, N.J., assignors to Merck & Co., Inc., Railway, N.J., acorporation of New Jersey No Drawing. Filed July 3, 1962, Ser. No.207,406

5 Claims. (Cl. 260-556) This invention relates to a process for theproduction of 5H-dibenzo[a,d]cycloheptenes. In particular, the inventionrelates to the preparation of 5H-dibenzo[a,d]- cycloheptenes which aresubstituted at the 5-position with a secondary aminopropyl. Moreparticularly, the invention is concerned with the preparation of5-(3-methy1- aminopropyl -5H-dibenzo [-a,d] cycloheptene. The inventionalso relates to novel compounds utilized in the process and theirpreparation.

In accordance with the process of the present invention, an alkali metalderivative of SH-dibenz-o[a,d]cycloheptene is reacted with anN-(3-halopropyl)-N-methyl-hydrocarbonsulfonamide and the resulting5-[3-(N-hydrocarbonsulfonyl-N-methyl) aminopropyl]-5H-dibenzo[a,d]-cycloheptene transformed into the desired product. This process may beillustrated as follows:

wherein M represents an alkali metal such as sodium, potassium orlithium; R is a radical selected from the group consisting of alkyl,cycloalkyl, aralkyl and aryl and X is a halogen, preferably chlorine orbromine. The compounds may also have substituents on one or both of thebenzenoid rings and/or on the propyl chain. It will be readily apparentto those skilled in the art that inasmuch as the R group is removedduring the process, it is not critical which particular group isutilized to form the N (3-halopropyl)-N-methylhydrocarbonsulfonarnide orintermediate dibenzocycloheptene and the choice thereof is subject onlyto the limitations of ease of splitting of the sulfonamide intermediateand other practical and economical considerations. However, thepreferred groups in each instance are alkyl or aryl.

The starting compound, namely, the alkali metal derivative of5H-dibenzo[a,d]cycloheptene may be readily prepared by reactingSH-dibenzo[a,d]cycloheptene with a metalating reagent such as, forexample, sodium amide, potassium amide, phenylsodium, butyllithium andthe like. The sodium and potassium derivatives may be prepared using theprocess described by Villani, J. Med. and Pharm. Chem. 5, pp. 373-382(1962). derivative may be prepared in analogous manner usingbutyllithium.

The N (3-halopropyl)-N-methylhydrocarbonsulfonamides may be prepared byreacting a l-halo-3-halopropane with an alkali metal salt of anN-methylhydrocarbonsulfonamide. This may be illustrated as follows:

SOzR

The lithium wherein X, M and R are as previously defined. In the case ofthe dihalopropane reactant, the X substituents may be the same ordifferent. However, as pointed out hereinabove, although R is preferablyan alkyl or aryl radical, it is not critical which particular group isutilized to form the sulfonamide reactant since this group issubsequently removed during the process. The reaction is suitablycarried out in the presence of an inert, substantially anhydrous organicmedium which is suitable as a solvent for the sulfonamide salt.Representative solvents include formamide, dimethylformamide,dimethylacetamide and dimethylsulfoxide. The temperature at which thereaction is carried out is not critical. The reaction may be carried outat room temperature or elevated temperatures up to the refluxtemperature of the system. Likewise, the ratio of reactants is notcritical and equimolar amounts may be used although it is preferred toemploy a slight excess of the sulfonamide salt. After completion of thereaction, the solvent is removed and the desired product recovered.Further purification of the product can be achieved byrecrystallization.

An alternate procedure for preparing the above sulfonamides involvesreacting a 1-hydrocarbonsulfonyloxy- 3-halop1'opane with an alkali metalsalt of an N-methylhydrocarbonsulfonamide. This process may berepresented as follows:

XCH2CH2CH2OSO2R' +MN H Method B CH XCHzCHzCHzN wherein X, M and R are aspreviously defined. In this procedure, R is as defined for R, and R andR may be similar or dissimilar. The'reaction conditions are the same asdescribed for Method A.

The l-hydrocarbonsulfonyloxy-3-halopropanes can be prepared by reactinga 3-halopropanol-1 with a hydrocarbonsulfonyl halide using known methodsheretofore described in the literature,

The reaction between the alkali metal derivative ofSH-dibenzo[a,d]cycloheptene and the N-(3-halopropyl)-N-methylhydrocarbonsulfonamide is carried out in an inert, substantiallyanhydrous organic solvent. The choice of solvent is not critical and awide variety can be utilized. Representative of these are the aromatichydrocarbons such as benzene, toluene and the like; aliphatichydrocarbons such as heptene, hexane and the like; ethers such asdiethylether, diamylether and the like. The temperature at which thereaction is carried out is not critical. The reaction may be carried outat room temperature or elevated temperatures up to the refluxtemperature of the system. Likewise, the ratio of reactants is notcritical and equimolar amounts may be used. After completion of thereaction, the solvent is removed and the 5-[3-(N- hydrocarbonsulfonyl Nmethyl)-aminopropyl]-5H-dibenzo[a,d]cycloheptene recovered. Furtherpurification of the product can be achieved by crystallization.

Conversion to the 5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene isaccomplished employing the conventional methods for the splitting ofsulfonamides as, for example, by treatment with hydrobromic acid inacetic acid in the presence of phenol or by reductive splitting withliquid ammonia in the presence of sodium metal.

The end compound, namely, 5-(3-methylaminopropyl)- 5:H-dibenzo[a,d]cycloheptene, prepared by the process of the present invention, isuseful in the treatment of mental health conditions as it is ananti-depressant and serves as a mood elevator or a psychic energizer.For this purpose,

the daily dosage is within the range of 5-250 mg, preferably taken individed amounts over the day.

The following examples are given for purposes of i1- lustrating thepresent invention and are not to be,construed as limiting the invention.

Example 1.Preparatin of N-(3-chl0r0pr0pyl)-N-met/1yl-p-tolaenesulfonam'ide To a mixture containing 20.7 g. (0.1 mole)of the sodium salt of N-met'hyl-p-toluenesulfonamide and 4 g. sodiumiodide in 150 ml. of dimethylformamide is added 15.8 g. (0.1 mole) of1-chloro-3-bromopropane and the mixture heated at 120 C. with stirringfor 36 hours. The solvent is distilled ofl? in vacuo and, after theaddition of water, the solid product is recovered by filtration.

Example 2 Example 3.-Alternate preparation of N-(3-chl0r0-propyl)-N-methyl-p toluenesulfonamide.

17.2 G. of 3-chloro-1-methylsulfonyloxypropane is added to a mixturecontaining 20.7 g. (0.1 mole) of the sodium salt ofN-methylap-toluenesulfonarnide in 100 ml. of dimethylformamide and themixture stirred at 100 C. for 20 hours. The solvent is distilled off invacuo and 200 ml. of water added to the residue and the productrecovered by filtration.

Example 4 Following the procedure of Example 3 and employing3-chloro-l-phenylsulfonyloxypropane, 3-chloro-l-benzylsulfonyloxypropaneand 3-chloro-l-p-:tolylsulfony1oxypropane in place of3-chloro-l-methyl-sulfonyloxypropane, there is obtained the same productofExample 3.

Example 5.Preparation of 5- [3-(N-methyl-N-p-toluenesulfonyl)-amin0pr0pyl] -5H-dibenz0[a,d] cycloheptene To a suspension of 3.9 g. ofpotassium amide is slowly added a solution of 19.2 g. (0.1 mole) ofSH-dibenzo [a,d]cycloheptene in 600 ml. of ether with stirring. Thesuspension is refluxed with stirring for 3 hours, then cooled to roomtemperature and 32.05 g. of N-(3-chloro-propyl)-N-methyl-p=toluenesulfonamide and 5 g. of sodium iodide is added. Theether is distilled off and 200 ml. of diethyleneglycol dimethylether isadded and the mixture heated with stirring at 80 C. for 12 hours. Thediethyleneglycol dimethylether is evaporated in vacuo and 100 ml. ofwater and 100 ml. of ether added. The ether layer is then washed withdilute hydrochloric acid, then water and then dried over magnesiumsulfate and evaporated to dryness yielding 5-[3-(N-methyl-N-p-toluenesulfonyl) -aminopropyl] -5H-dibenzo a,d]cycloheptene.

Example 6 4 benzylsulfonyl N-methyl)-aminopropyl]-5H-dibenzo[a, d]-cyclohepter1e, respectively.

Example 7.-Preparati0n of 5-(3-methylamin0p'r0pyl)-5H-dibenzo[a,d]cycloheptene froml 5-[3-(N-methyl-N- ptoluenesulfonyl)-amin0pr0pyl]-5H-dibenz0[a,zi]cycloheptene 4.2 G. of5-[3-(N methyl-N-p-toluenesulfonyl)-aminopropyl]-5H-di'benzo[a,d]eycloheptene is added to ml. of liquid ammonia and then2 g. of sodium metal is added in small pieces while stirring vigorously,and cooling using a water-tbath. After 6 hours-of stirring, 8 g. ofammonium chloride is added. After the deep blue color which initiallyforms disappears, cooling is stopped and the ammonia left to evaporate.50 ml. of water is added and the mixture alkalized with dilute sodiumhydroxide solution and the 5-(3-methylaminopropyl) -5H-dibenzo[a,d]cycloheptene extracted with benzene, and the benzene evaporated off.Further purification can be achieved by forming the oxalic acid salt.

Example 8 Following the procedure of Example 7 and employing equivalentquantities of 5 [3 (N-benzenesulfonyl-N- methyl) aminopropyl]5H-di!benzo[a,d]cycloheptene, 5- [3 (Nmethyl-N-methylsulfonyl)-aminopropyl]-5H-dibenzo[a,d] cycloheptene and5- [S-(N-benzylsulfonyl-N- methyl)aminopropyl]-5H-dibenzo[a,d]cycloheptene in place of5-[3-(N-miethyl-N-p-toluenesulfonyl)-aminopropyl]-5H-dibenzo[a,d]cycloheptene,there is similarly obtained 5(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene.

We claim:

1. 5 [3 (N methyl-N-p-toluenesulfonyl)-aminopropyl] -5H-dibenzo a,d]cycloheptene.

2. 5 [3 (N-hydrocarbonsulfonyl-N-methyl)-aminopropyl]-5H-dibenzo[a,'d]cycloheptene wherein the hydrocarbon moiety of said hydrocarbonsulfonylis tolyl, benzyl, phenyl or methyl.

3. 5 [3 (N-hydrocarbonsulfonyl-N-methyl)-aminopropyl]-5H-dibenzo[a,d]cycloheptene, wherein the hydrocarbon moiety of saidhydrocarbonsulfonyl group is alkyl, cycloalkyl, aralkyl or arylcontaining up to about 7 carbons.

4. 5 [3(N-hydrocarbonsulionyl-N-methyl)-aminopropyl]-5I-I-dibenzo[a,d]cycloheptene,wherein the hydrocarbon moiety of said hydrocarbonsulfonyl group islower alkyl.

5. 5 [3(N-hydrocarbonsulfonyl-N-methyl)-aminopropyl]-5H-dibenzo[a,d]cycloheptene,wherein the hydrocarbon moiety of said hydrocarbonsulfonyl group is arylor aralkyl containing no more than 7 carbons.

References Cited by the Examiner UNITED STATES PATENTS 2,475,424 7/ 1949Dickey et al. 260 -556 2,663,732 12/1953 Weissberger 260-556 2,794,8346/ 1957 Randall et a1 260-556 2,985,660 5/1961 Judd et al. 260--313OTHER REFERENCES Houben-Weyl, Methoden der Organischen Chemio, 4th ed.,Band XI/ 1, pages 98-100 and 941-947, Georg Thieme Verlag, Stuttgart,Germany (1957).

JOHN D. RANDOLPH, Primary Examiner.

IRVING MARCUS, Examiner.

WALTER A. MODANCE, E. E. BERG,

Assistant Examiners.

1. 5 - (3 -(N-METHYL-N-P-TOLUENESULFONYL)-AMINOPROPYL)-5H-DIBENZO(A,D)CYCLOHEPTENE.2. 5 - (3 -(N-HYDROCARBONSULFONYL-N-METHYL)-AMINOPROPYL)-5H-DIBENZO(A,D,)CYCLOHEPTENEWHEREIN THE HYDROCARBON MOIETY OF SAID HYDROCARBONSULFONYL IS TOLYL,BENZYL, PHENYL OR METHYL.